Factor Xa is a member of the trypsin-like serine protease class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospholipid forms the prothrombinase complex, which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin, which polymerizes to form insoluble fibrin. Factor Xa can be activated by two distinct complexes, by tissue factor-VIIa complex on the “Xa burst” pathway and by the factor IXa-VIIIA complex (TENase) of the “sustained Xa” pathway in the coagulation cascade. After vessel injury, the “Xa burst” pathway is activated via tissue factor (TF). Up regulation of the coagulation cascade occurs via increased factor Xa production via the “sustained Xa” pathway. Down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFPI complex, which not only removes factor Xa but also inhibits further factor formation via the “Xa burst” pathway. Therefore, the coagulation cascade is naturally regulated by factor Xa.
The primary advantage of inhibiting factor Xa over thrombin in order to prevent coagulation is the focal role of factor Xa versus the multiple functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor VIII to VIIIA, factor V to Va, and factor XI to XIa, but also activates platelets, is a monocyte chemotactic factor, and mitogen for lymphocytes and smooth muscle cells. Thrombin activates protein C, the in vivo anti-coagulant inactivator of factors Va and VIIIa, when bound to thrombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin III (ATIII) and heparin cofactor II (HCII) in a reaction which is catalyzed by heparin or other proteolycan-associated glycosaminoglycans, whereas thrombin in tissues is inactivated by the protease, nexin. Thrombin carries out its multiple cellular activation functions through a unique “tethered ligand” thrombin receptor (Cell 1991; 64: 1057), which requires the same anionic binding site and active site used in fibrinogen binding and cleavage and by thrombomodulin binding and protein C activation. Thus, a diverse group of in vivo molecular targets compete to bind thrombin and the subsequent proteolytic events will have very different physiological consequences depending upon which cell type and which receptor, modulator, substrate or inhibitor binds thrombin.
U.S. Pat. No. 5,576,343 describes aromatic amidine derivatives as anticoagulants and also as inhibitors of Factor Xa. U.S. Pat. No. 5,691,364 describes benzamidine derivatives as anti-coagulants.
WO9900121 describes 1,2-diamino compounds as inhibitors of Factor Xa. U.S. Pat. No. 6,140,351 describes ortho anthranilamide derivatives as anticoagulants. WO2004026816 describes aromatic benzoate derivatives as Liver X-receptor modulators. WO0119788 describes benzamide and related inhibitors of Factor Xa
However, the therapeutic potential of these compounds to treat diseases has not yet been proved and so there remains the need to develop newer medicines which are better or of comparable efficacy with the present treatment regimes, have lesser side effects and require a lower dosage regime
We herein disclose novel compounds of formula (I) which shows a strong anticoagulant effect through its highly specific and reversible FXa-inhibiting activity and is useful as a drug for the prevention and treatment of various thrombosis- and embolism-based diseases
The inventive compounds of the present invention have a high anticoagulant capacity based on its excellent FXa inhibition activity. The invention also relates to an anticoagulant, or a thrombosis- or embolism preventing or treating agent that contains the sulfoximine derivative or a salt thereof of the present invention as an active ingredient. This invention is also directed to pharmaceutical compositions containing the compounds of the invention and methods of using the compounds to treat disease-states characterized by thrombotic activity.